A number of imidazopyrazine compounds are under investigation for inhibiting Spleen Tyrosine Kinase (Syk) activity. Syk is a non-receptor tyrosine kinase that plays critical roles in immunoreceptor- and integrin-mediated signaling in a variety of cell types, including B-cells, macrophages, monocytes, mast cells, eosinophils, basophils, neutrophils, dendritic cells, T-cells, natural killer cells, platelets, and osteoclasts.
Syk has been reported to play an important role in signaling through the B-cell receptor, known to be an important survival signal in B-cells. As such, inhibition of Syk activity may be useful for treating certain types of hematologic malignancies. Examples of such hematologic malignancies include cancer, such as B-cell lymphoma and leukemia. Additionally, the inhibition of Syk activity is believed to be useful for treating of other diseases and conditions, including inflammatory diseases (e.g., rheumatoid arthritis), allergic disorders and autoimmune diseases.
One such compound that has been found to inhibit Syk activity is represented by formula I:
or a pharmaceutically acceptable salt thereof. This compound, also known as entospletinib, and its synthesis have been described in U.S. Pat. Nos. 8,450,321 and 8,455,493, which are hereby incorporated by reference in their entirety and specifically with respect to the method of making this compound. See e.g., U.S. Pat. No. 8,450,321, Examples 1 and 2.
It has been known that certain genomic aberrations are associated with resistance to treatment of B-cell lymphomas and leukemias, such as in the case of a 17p deletion, a TP53 mutation, a NOTCH1 mutation, a SF3B1 mutation, a 11q deletion, or any combination thereof, in patients experiencing chronic lymphocytic leukemia (CLL). Articles discussing the issue include 17p Deletion is associated with resistance of B-cell chronic lymphocytic leukemia cells to in vitro fludarabine-induced apoptosis, Turgut et al., Leukemia & Lymphoma, 2007, Vol. 48, No. 2: Pages 311-320; Mutations of NOTCH1 are an independent predictor of survival in chronic lymphocytic leukemia, Rossi et al., Blood, 2012, 119, pp. 521-529; TP53 Mutation and Survival in Chronic Lymphocytic Leukemia, Zenz et al., J. of Clin. Oncol., Vol. 28, No. 29, Oct. 10, 2010, pp. 4473-4479; SF3B1 and Other Novel Cancer Genes in Chronic Lymphocytic Leukemia, Wang et al., N Engl J Med 2011, 365, pp. 2497-2506; and Mutation Status of the Residual ATM Allele Is an Important Determinant of the Cellular Response to Chemotherapy and Survival in Patients With Chronic Lymphocytic Leukemia Containing an 11q Deletion, Austen et al., J. of Clin. Oncol., Vol. 25, No. 34, Dec. 1, 2007, pp. 5448-5457.
The Syk inhibitor fostamatinib was proposed as a therapy for B-cell malignancies on the basis of targeting Syk kinase (Sharman et al., J Clin Oncol. 2007; 25(suppl 18S)). Response rate to fostamatinib was reported as 54.5% based upon six subjects experiencing a partial lymph-node reduction of at least 50%. Unfortunately, fostamatinib treatment was associated with a relatively brief overall progression-free survival (PFS) of 18 weeks seen among participants treated in the phase 2 portion of the study, and PFS was 6.4 months for 11 subjects with CLL/SLL (Friedberg et al., Blood. 2010; 115(13):2578-2585). Further clinical development of fostamatinib has not been reported, and dose-limiting adverse events (AEs) possibly resulting from off-target activity of the agent highlight the need for more Syk-selective agents.
What is desired are methods for treating diseases responsive to the inhibition of Syk in subjects in need of such treatment, including in subjects who may be considered at risk for the disease, are refractory to standard treatments, and/or are in relapse after standard treatments, including those subjects with genomic aberrations that may be associated with resistance to treatments.